The present invention relates to a novel use of a prostanoic acid compound wherein the skeletal carbon atoms in xcex1-chain are increased as endothelin antagonist.
The antagonist according to the present invention is useful as a treating agent for a variety of diseases participated of endothelin.
Endothelin is an endogenous bioactive peptide composed of 21 amino acids, and three types of which, i.e., endothelin-1, endothelin-2, and endothelin-3 are known.
Endothelin is a bioactive substance for continuously constricting vascular or non-vascular smooth muscle in direct or indirect way (regulation of release of a variety of endogenous substances), and production of endothelin increases due to lesion of endothelium. Excessive production of endothelin is considered-to be a cause for diseases such as hypertension, pulmonary hypertension, Buerger disease, primary Raynaud syndrome, asthma, eyegrounds (amphiblestrodes, chorioidea, and the like) diseases, diabetes, arterial sclerosis, renal failure, cardiac infarction, angina pectoris, cerebrovascular contraction, and cerebral infarction. Furthermore, it is known that endothelin is an important mediator with respect to multiple organ failures, and diseases such as disseminated intravascular coagulation due to endotoxin shock and the like as well as renal lesion induced by cyclosporin and the like. Moreover, it is also known that an endothelin concentration in blood increases after organ transplantation such as liver transplant.
Prostanoic acid is a skeletal compound constituting a common structural feature of natural prostaglandins (PG) groups and is represented by the following structural formula: 
Natural PG groups are classified based on the structural feature of five-membered ring into PGA group, PGB group, PGC group, PGD group, PGE group, PGF group, PGG group, PGH group, PGI group, and PGJ group; and further they are classified as follows on the basis of presence or absence of unsaturation and oxidation at their chain portions:
numerical subscript 1 . . . 13,14-unsaturated-15-OH
numerical subscript 2 . . . 5,6- and 13,14-di-unsaturated-15-OH
numerical subscript 3 . . . 5,6,13,14- and 17,-18-tri-unsaturated-15-OH
Moreover, the PGF group is classified into a (hydroxy group is in alpha-configuration) and xcex2 (hydroxy group is in beta-configuration) based on the configuration of hydroxy group at 9-position. In addition, a compound having oxo group in place of hydroxy group at 15-position is also known.
With respect to action of prostanoic acid compound on endothelin, it has been reported, for example, that PGE2 inhibits renal endothelin inducible vasoconstriction in rat, and that prostacyclin (PGI2) moderates renal endothelin inducible vasoconstriction in dog.
However, any of these prostanoic acid compounds is the one wherein the basic carbon atoms in xcex1-chain are 7, and hence, they do not correspond to the prostanoic acid compound wherein the skeletal carbon atoms in xcex1-chain increase.
U.S. Pat. No. 3,974,195 and European Patent Application Laid-Open No. 0453127 (corresponding to Japanese Patent Kokai Hei 5-58992) describe a compound wherein the skeletal carbon atoms in xcex1-chain are increased by 2, but there is no description as to the action with respect to endothelin in these both publications.
An object of the present invention is to provide an endothelin antagonist useful for treating a variety of diseases and pathologies participated of endothelin.
The present inventor has eagerly studied with respect to biological activity of a prostanoic acid compound wherein the skeletal carbon atoms in xcex1-chain are increased. As a result, it has been surprisingly found that a prostanoic acid compound wherein the skeletal carbon atoms in xcex1-chain are increased has extremely strong antagonistic action as compared with that of a heretofore known prostanoic acid compound having 7 skeletal carbon atoms in xcex1-chain, so that the present invention has been completed.
More specifically, the present invention provides an endothelin antagonist comprising a prostanoic acid compound having 8 or more skeletal carbon atoms in xcex1-chain as an active ingredient.
As used herein, the term xe2x80x9ca prostanoic acid compound having 8 or more skeletal carbon atoms in xcex1-chainxe2x80x9d includes any of substituted compounds and derivatives of a compound wherein the skeletal carbon atoms in xcex1-chain of prostanoic acid are increased""so that the skeletal carbon atoms in xcex1-chain are 8 or more, irrespective of the structure of five-membered ring, the number of double bond on xcex1- or xcfx89-chain, presence or absence of hydroxy group, oxo group, and the other substituents as well as any modification of chained portion.
Nomenclature of the prostanoic acid compounds herein uses the numbering system of the prostanoic acid represented in the formula (A) shown above.
While formula (A) shows a basic skeleton having twenty carbon atoms, the carbon atoms in the present invention are not limited thereto. Namely, the numbers of the carbons constituting the basic skeleton are assigned in such that number 1 is assigned to carboxylic acid, numbers 2 to 7 are given to the carbons on the xcex1-chain in accordance with the order directing to the five-membered ring, numbers 8 to 12 are assigned to the carbons of the five-membered ring, and numbers 13 to 20 are given to the carbons on the xcfx89-chain, respectively. However, in the case where carbon atoms decrease on the xcex1-chain, numbers are successively deleted from the 2-position, while in the case where carbon atoms increase on the xcex1-chain, nomenclature is made in such that the 2-position is substituted by any substituent in place of the carboxyl group (1-position). Likewise, in case of decreasing carbon atoms on the xcfx89-chain, the number of carbon atoms is successively deleted from 20-position, while in case of increasing carbon atoms on the xcfx89-chain, nomenclature is made in such that the carbon atoms at 21- and thereafter positions are considered to be substituents. Further, with respect to steric configuration, it is in accordance with that involved in the above indicated basic skeleton unless otherwise specified.
For instance, while PGD, PGE, and PGF mean compounds each containing hydroxy group(s) at 9-position and/or 11-position, the present invention includes also compounds containing any other group(s) in place of hydroxy group(s) at 9-position and/or 11-position. In case of nomenclature of these compounds, it is made in the form of 9-dehydroxy-9-substituted compound or 11-dehydroxy-11-substituted compound. In case of containing hydrogen in place of hydroxyl group, it is simply named as 9(11)-dehydroxy compound.
As mentioned above, while nomenclature of prostanoic acid compound is made on the basis of prostanoic acid skeleton in the present invention, when the above described compound has the same partial structure as that of prostaglandins, there is a case where an abbreviation of PG is also utilized for simplicity. In such case, a PG compound having two increased skeletal carbon atoms in xcex1-chain, i.e., a PG compound having 9 skeletal carbon atoms in xcex1-chain is named as 2-decarboxy-2-(2-carboxyethyl)-PG compound. Likewise, a PG compound having 11 skeletal carbon atoms in xcex1-chain is named as 2-decarboxy-2-(4-carboxybutyl)-PG compound. Furthermore, a PG compound having two increased skeletal carbon atoms in xcfx89-chain, i.e., a PG compound having 10 skeletal carbon atoms in xcfx89-chain is named as 20-ethyl-PG compound. The naming may also be made based on IUPAC nomenclature. Examples of naming according to both the nomenclature are shown in the following Examples.
The prostanoic acid compounds used in the present invention are the ones wherein the skeletal carbon atoms in xcex1-chain may be 8 or more, preferably 8 to 13, more preferably 9 to 13, and particularly preferably 9 to 11. Accordingly, any of the following compounds may be used, and they are, for example, PG1 compounds having double bonds at 13-14 positions and a hydroxy group at 15-position, PG2 compounds having further double bonds at 5-6 positions, PG3 compounds having further double bonds at 17-18 positions, 15-keto-PG compounds having further an oxo group in place of hydroxy group at 15-position, 15-dehydroxy-PG compounds having hydrogen in place of hydroxy group at- 15-position, or either 13,14-dihydro-PG compounds wherein these double bonds at 13-14 positions are single bonds, or 13,14-didehydro-PG compounds wherein the double bonds at 13-14 positions are triple bonds. Moreover, examples of substituted compounds and derivatives include compounds wherein the terminal carboxyl group in xcex1-chain of the above described prostanoic acid compound containing 8 or more skeletal carbon atoms in xcex1-chain has been esterified, the physiologically acceptable salts thereof, compounds wherein the carbon atoms in xcfx89-chain are increased, compounds having side chains (e.g., 1 to 3 carbon atoms) on xcex1- and xcfx89-chains, compounds having substituent(s) such as hydroxy, halogen, lower alkyl, hydroxy(lower)alkyl, and oxo, or double bond(s) on the five-membered ring, compounds having substituent(s) such as halogen, oxo, and aryl on xcex1-chain, compounds having substituents such as halogen, oxo, hydroxy, lower alkoxy, lower alkanoyloxy, cyclo(lower)alkyl, aryl, and aryloxy on xcfx89-chain, and compounds having substituent such as lower alkoxy, lower alkanoyloxy, cyclo(lower)alkyl, aryl, and aryloxy at the terminal of the xcfx89-chain of which is shorter than that of normal prostanoic acid.
A preferred compound used in the present invention is represented by the formula (I): 
wherein L and M are hydrogen, hydroxy, halogen, lower alkyl, hydroxy(lower)alkyl, or oxo wherein at least one of L and M is a group other than hydrogen, and the five-membered ring may have at least one double bond;
A is xe2x80x94CH2OH, xe2x80x94COCH2OH, xe2x80x94COOH or its functional derivatives;
B is xe2x80x94CH2xe2x80x94CH2xe2x80x94, xe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94Cxe2x89xa1Cxe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94, xe2x80x94CHxe2x95x90CHxe2x80x94CH2xe2x80x94, xe2x80x94CH2xe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94Cxe2x89xa1Cxe2x80x94CH2xe2x80x94, or xe2x80x94CH2xe2x80x94Cxe2x89xa1Cxe2x80x94;
Z is 
wherein R4 and R5 are hydrogen, hydroxy, lower alkyl, or lower alkoxy wherein R4 and R5 are not hydroxy and lower alkoxy at the same time;
R1 is a divalent saturated or unsaturated aliphatic hydrocarbon residue having 7 to 12 carbon atoms, which is unsubstituted or substituted by halogen, oxo, or aryl; and
Ra is a saturated or unsaturated lower-medium aliphatic hydrocarbon residue which is unsubstituted or substituted by halogen, oxo, hydroxy, lower alkoxy, lower alkanoyloxy, cyclo(lower)alkyl, aryl, or aryloxy.
A group of particularly preferable compounds among the above described compounds is represented by the general formula (II): 
wherein L and M are hydrogen, hydroxy, halogen, lower alkyl, hydroxy(lower)alkyl, or oxo wherein at least one of L and M is a group other than hydrogen, and the five-membered ring may have at least one double bond;
A is xe2x80x94CH2OH, xe2x80x94COCH2OH, xe2x80x94COOH or its functional derivatives;
B is xe2x80x94CH2xe2x80x94CH2xe2x80x94, xe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94Cxe2x89xa1Cxe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94, xe2x80x94CHxe2x95x90CHxe2x80x94CH2xe2x80x94, xe2x80x94CH2xe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94Cxe2x89xa1Cxe2x80x94CH2xe2x80x94, or xe2x80x94CH2xe2x80x94Cxe2x89xa1Cxe2x80x94;
Z is 
wherein R4 and R5 are hydrogen, hydroxy, lower alkyl, or lower alkoxy wherein R4 and R5 are not hydroxy and lower alkoxy at the same time;
X1 and X2 are hydrogen, lower alkyl, or halogen;
R1 is a divalent saturated or unsaturated aliphatic hydrocarbon residue having 7 to 12 carbon atoms, which is unsubstituted or substituted by halogen, oxo, or aryl;
R2 is a single bond or lower alkylene; and
R3 is lower alkyl, lower alkoxy, cyclo(lower)alkyl, aryl, or aryloxy.
Furthermore, the present invention relates to a compound represented by the general formula (III): 
wherein L and M are hydrogen, hydroxy, halogen, lower alkyl, hydroxy(lower)alkyl, or oxo wherein at least one of L and M is a group other than hydrogen, and the five-membered ring may have at least one double bond;
Axe2x80x2 is xe2x80x94COOH, or its functional derivatives;
Bxe2x80x2 is xe2x80x94CH2xe2x80x94CH2xe2x80x94, or xe2x80x94CHxe2x95x90CHxe2x80x94;
Zxe2x80x2 is 
X1 and X2 are hydrogen, lower alkyl, or halogen wherein at least one of X1 and X2 is a halogen;
R1 is a divalent saturated or unsaturated aliphatic hydrocarbon residue having 8 carbon atoms, which is unsubstituted or substituted by halogen, oxo, or aryl;
R2 is a single bond or lower alkylene; and
R3 is lower alkyl, lower alkoxy, cyclo(lower)alkyl, aryl, or aryloxy.
Moreover, the present invention relates to a compound represented by the general formula (IV): 
wherein L and M are hydrogen, hydroxy, halogen, lower alkyl, hydroxy(lower)alkyl, or oxo wherein at least one of L and M is a group other than hydrogen, and the five-membered ring may have at least one double bond;
Axe2x80x3 is xe2x80x94COOH, or its functional derivatives;
Bxe2x80x3 is xe2x80x94CH2xe2x80x94CH2xe2x80x94, or xe2x80x94CHxe2x95x90CHxe2x80x94;
Zxe2x80x3 is 
X1 and X2 are hydrogen, lower alkyl, or halogen;
R1xe2x80x3 is a divalent saturated or unsaturated aliphatic hydrocarbon residue having 8 carbon atoms, which is unsubstituted or substituted by halogen, oxo, or aryl;
R2 is a single bond or lower alkylene; and
R3 is lower alkyl, lower alkoxy, cyclo(lower)alkyl, aryl, or aryloxy.
Still further, the present invention relates to a compound represented by the general formula (V): 
wherein L and M are hydrogen, hydroxy, halogen, lower alkyl, hydroxy(lower)alkyl, or oxo wherein at least one of L and M is a group other than hydrogen, and the five-membered ring may have at least one double bond;
Axe2x80x3xe2x80x2 is xe2x80x94COOH, or its functional derivatives;
Bxe2x80x3xe2x80x2 is xe2x80x94CH2xe2x80x94CH2xe2x80x94, or xe2x80x94CHxe2x95x90CHxe2x80x94;
Zxe2x80x3xe2x80x2 is 
X1 and X2 are hydrogen, lower alkyl, or halogen;
R1xe2x80x3xe2x80x2 is a divalent saturated or unsaturated aliphatic hydrocarbon residue having 10 carbon atoms, which is unsubstituted or substituted by halogen, oxo, or aryl;
R2 is a single bond or lower alkylene; and
R3 is lower alkyl, lower alkoxy, cyclo(lower)alkyl, aryl, or aryloxy.
In the above described formula, the term xe2x80x9cunsaturatedxe2x80x9d appeared in R1, R1xe2x80x2, R1xe2x80x3, R1xe2x80x3xe2x80x2, and Ra means to include at least one or more of double bond(s) and/or triple bond(s) isolatedly, separately, or serially present between carbon atoms of the straight or side chain.
The term xe2x80x9clower-medium aliphatic hydrocarbonxe2x80x9d means a hydrocarbon having a straight chain of 1 to 14 carbon atoms which may have side chain (wherein the side chain has preferably 1 to 3 carbon atoms), and preferably, 1 to 9 carbon atoms.
The term xe2x80x9caliphatic hydrocarbon having 7 to 12 carbon atomsxe2x80x9d means a hydrocarbon having a straight chain of 7 to 12 carbon atoms which may have side chain (wherein the side chain has preferably 1 to 3 carbon atoms). Preferable is such that the hydrocarbon has 8 to 12 carbon atoms, and particularly preferable is such that the hydrocarbon has 8 to 10 carbon atoms.
The term xe2x80x9chalogenxe2x80x9d includes fluorine, chlorine, bromine, and iodine.
The term xe2x80x9clowerxe2x80x9d means a group having 1 to 6 carbon atoms unless otherwise specified.
The term xe2x80x9clower alkylxe2x80x9d means a straight- or branched-chain saturated hydrocarbon group having 1 to 6 carbon atoms, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, and hexyl.
The term xe2x80x9clower alkoxyxe2x80x9d means a lower alkyl-Oxe2x80x94 wherein the lower alkyl is as described above.
The term xe2x80x9chydroxy(lower)alkylxe2x80x9d means an alkyl as described above, which is substituted by at least one hydroxy group, for example, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, and 1-methyl-1-hydroxyethyl.
The term xe2x80x9clower alkanoyloxyxe2x80x9d means a group represented by the formula RCOxe2x80x94Oxe2x80x94 wherein RCOxe2x80x94 is an acyl formed by oxidation of a lower alkyl as described above, for example, acetyl.
The term xe2x80x9clower cycloalkyl groupxe2x80x9d means a group formed by cyclization of a lower alkyl group containing 3 or more carbon atoms as described above, for example, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
The term xe2x80x9carylxe2x80x9d includes aromatic hydrocarbon rings or heterocyclic groups (preferably monocyclic groups) which may be substituted, for example, phenyl, tolyl, xylyl, and thienyl. An example of the substituent in this case includes halogen, and halogen substituted lower alkyl group (wherein halogen atom and lower alkyl group are as described above).
The term xe2x80x9caryloxyxe2x80x9d means a group represented by the formula ArOxe2x80x94 (wherein Ar is an aryl group as described above).
The term xe2x80x9cfunctional derivativesxe2x80x9d of the carboxy group represented by A includes salts (preferably pharmaceutically acceptable salts), esters, and amides.
Examples of suitable xe2x80x9cpharmaceutically acceptable saltsxe2x80x9d include nontoxic salts which are commonly used, and they are salts with inorganic bases, for example, alkali metal salts (sodium salt, potassium salt and the like); alkaline earth salts (calcium salt, magnesium salt and the like); ammonium salts; salts with organic bases, for example, amine salts (such as methylamine salt, dimethylamine salt, cyclohexylamine salt, benzylamine salt, piperidine salt, ethylenediamine salt, ethanolamine salt, diethanolamine salt, triethanolamine salt, tris(hydroxymethylamino)ethane salt, monomethyl-monoethanolamine salt, lysine salt, procaine salt, and caffeine salt); basic amino acid salts (such as arginine salt, and lysine salt); tetraalkyl ammonium salts and the like. These salts may be manufactured from, for example, corresponding acids and bases in accordance with a conventional manner or salt exchange.
The esters includes aliphatic esters, for example, lower alkyl esters such as methyl ester, ethyl ester, propyl ester, isopropyl ester, butyl ester, isobutyl ester, t-butyl ester, pentyl ester, and 1-cyclopropylethyl ester; lower alkenyl esters such as vinyl ester, and allyl ester; lower alkynyl esters such as ethynyl ester, and propynyl ester; hydroxy(lower)alkyl esters such as hydroxyethyl ester; and lower alkoxy(lower)alkyl esters such as methoxymethyl ester, and 1-methoxyethyl ester as well as, for example, optionally substituted aryl esters such as phenyl ester, tosyl ester, t-butylphenyl ester, salicyl ester, 3,4-dimethoxyphenyl ester, and benzamidephenyl ester; and aryl(lower)alkyl esters such as benzyl ester, trityl ester, and benzhydryl ester. An example of amides includes mono- or di-lower alkyl amides such as methylamide, ethylamide, and dimethylamide; aryl amides such as anilide, and toluidide; and alkyl or aryl sulfonyl amides such as methylsulfonyl amide, ethylsulfonyl amide, and tolylsulfonyl amide.
A preferred example of A-group includes xe2x80x94COOH, xe2x80x94COOCH3, xe2x80x94COOCH2CH3, xe2x80x94COOCH(CH3)2, and xe2x80x94CONHSO2CH3.
In the above described formula (I), configurations of the ring, xcex1- and/or xcfx89-chain(s) may be the same with or different from those of natural prostaglandins group. However, it is to be noted that the present invention includes also the mixtures of compounds having natural and nonnatural configurations.
An example of the typical compounds according to the present invention includes 2-decarboxy-2-(carboxy lower alkyl)-PG compounds, particularly 2-decarboxy-2-(2-carboxyethyl)-PG compound, 2-decarboxy-2-(4-carboxybutyl)-PG compound, 5-fluoro-form, 6-keto-form, 11-dehydroxy-form, 16-fluoro-form, 16-methyl-form, 17-fluoro-form, 17-methyl-form, 18-methyl-form, 19-methyl-form, 20-methyl-form, 20-ethyl-form, 20-propyl-form, 18,19,20-trinor-17-phenyl-form and the like.
In the PG compounds used in the present invention, when 13-,14-positions are saturated and 15-position is oxo (i.e., in case of 13,14-dihydro-15-keto-form), there is a case where keto-hemiacetal equilibrium occurs as a result of formation of hemiacetal between the hydroxy at 11-position and the keto at 15-position.
In the case when such tautomers exist, a ratio of existence of both the tautomers are depend upon the structure of the other party or the types of substituents, and according to circumstances, either of tautomers exists predominantly. However, the present invention includes these both tautomers, and there is a case where a compound is indicated in accordance with either keto-form structural formula or nomenclature irrespective of presence or absence of such tautomers. In other words, this is only a manner for conveniences"" sake, and there is no intention of excluding hemiacetal-form compounds.
In the present invention, any of the individual tautomers, the mixture thereof, or optical isomers, the mixtures thereof, racemic modifications, and other isomers such as stereoisomers may be used for the same purpose.
While the compounds according to the present invention can be manufactured by a variety of methods, they may also be manufactured, for example, in accordance with the following Synthetic Chart. In the following Synthetic Chart, P1, P2, P3, P4, P5, P6, and P7 are protective groups, and X1, X2, R2, and R3 are as described above. 
In the Synthetic Chart 1, with the compound (1) (wherein, for example, when X1 and X2 are hydrogens, respectively, the resulting compound corresponds to the Compound 8 shown in the Synthesis Chart I in page 37 of Japanese Patent Kokai Sho 64-52753) is reacted ylide obtained from (6-carboxyhexyl)triphenyl phosphonium bromide to produce the compound (2), it is esterified to obtain the compound (3), and the protective groups are removed therefrom to obtain the target compound (4). Furthermore, in the Reaction Formula 2, the above described compound (3) is subjected to Jones oxidation to prepare the compound (5), and from which are removed the protective groups to obtain the compound (6).
As another example, in the Synthetic Chart 3, the compound (8) prepared from the compound (7) (commercially available product) as a result of removing a protective group is subjected to Swan oxidation to produce the aldehyde-form (9), and with which is reacted 2-oxoheptyl phosphonate (e.g., 3,3-dihalo-form) to obtain the compound (10). The resulting compound (10) is catalytically reduced to prepare the compound (11), the ketone thereof is reduced with sodium hydrogenated boron to produce the compound (12), and is reduced with hydrogenated diisobutyl aluminum to obtain lactol (13). With which is reacted carboxyhexyl phosphonium bromide to prepare the compound (14), esterified to produce the compound (15), oxidized to produce the compound (16), and from which is removed a protective group to obtain the compound (6). If desired, the protective group for carboxyl group is removed to obtain the free acid (17). Moreover, in the Synthetic Chart 4, the above described compound (15) is catalytically reduce to prepare the compound (18), it is subjected to Swan oxidation to produce the compound (19), and from which is removed a protective group, whereby the target compound (20) can be obtained.
In the above described manufacturing methods, when the reduction by which the compound (1) is obtained from the compound (10) is omitted, a compound wherein B is xe2x80x94CHxe2x95x90CHxe2x80x94 is obtained.
In the general formula (I), when such compound is a target compound wherein M is a group other than OH (for example, a lower alkyl), lactone of the compound (12) wherein 11-position is released from the protection, while 15-position is protected is reduced to lactol, into which is introduced xcex1-chain in accordance with Wittig reaction, the hydroxy group at 11-position is protected by, for example, a lower alkane or a monocyclic aryl sulfonic acid group, then, is oxidized (for example, Jones oxidation) to obtain 10-en-9-on, and with which is reacted, for example, a lower alkyl copper complex to prepare 11-lower alkyl-form. PGD-type compounds are obtained by oxidation of the 11-nonprotective form, while PGA-type compounds are obtained from the 10-en-9-on form. Furthermore, 6-keto compound is obtained in such a manner, for example, as shown in the Synthetic Chart 5 that N-bromsuccinimide or iodine is reacted with the compound (3) to produce the compound (21), and the resulting compound is treated with DBU. 5,6-dehydro compound (i.e., acetylene-form) is obtained in such a manner, for example, as shown in the Synthetic Chart 6 that with a copper enolate prepared by reacting a copper complex with the compound (23) is reacted 8-alkoxycarbonyl-1-iodo-2-octine. A saturated xcex1-chain introducing agent is manufactured, for example, in accordance with the Synthetic Chart 7.
Furthermore, as another example, in the Synthetic Chart 8, the hydroxyl group at 15-position of the compound (12) is protected (by, for example, a silyl protective group) to prepare the compound (25), the lactone is reduced to lactol to obtain the compound (26), and with which is reacted an a-chain introducing agent, for example, an ylide prepared from (6-carboxyhexyl)triphenyl phosphonium bromide to obtain the compound (27). Then, the carboxyl group is protected to obtain the compound (28), the hydroxyl group at 9-position thereof is protected to prepare the composition (29), from the 15-position thereof the protective group is removed to obtain the compound (30), oxidized to produce the compound (31), and then, when from the 9- and 11-positions thereof are removed the protective groups, the target compound (32) is obtained.
Moreover, in the Synthetic Chart 9, the compound (14) in the Synthetic Chart 3 is protected by a protective group which can be removed by catalytic reduction (for example, benzyl) to prepare the compound (15), the 9-position thereof is oxidized, then, from the 11-position thereof is removed the protective group to obtain the compound (6), and when the resulting compound is catalytically reduced, a target compound (33) is obtained.
The above described prostanoic acid compounds containing 8 or more carbon atoms in xcex1-chain are useful as endothelin antagonist.
The compounds used in the present invention may be utilized as a pharmaceutical for animal and human being, and they may usually be administered systemically or locally in accordance with ophthalmic administration, oral administration, intravenous injection (including drip infusion), subcutaneous injection, intrarectal administration and the like manner. Especially, use in the form of eye drops is useful. Although the dosage varies dependent upon type, age, body weight, symptom to be treated, desired therapeutic effect, administration route, period to be treated or the like of objects such as animal or human being and the like, sufficient effect is ordinarily achieved by usually the dosage of 0.01 to 100 xcexcg/eye in case of local administration, or the dosage of 0.001 to 500 mg/kg in case of systemical administration in accordance with divided dose into two to four fractions per day or under sustained condition.
The ophthalmic preparations according to the present invention include ophthalmic solution or ophthalmic ointment and the like. Ophthalmic solution is prepared by either dissolving the active ingredient into sterile aqueous solution, for example, physiological saline, buffer solution and the like, or combining the former with the latter used at the time of administration. The ophthalmic ointment is prepared by mixing the active ingredient with a base.
The solid composition for oral administration used according to the present invention includes tablet, troche, sublingual tablet, capsule, pill, powder, granule and the like. In such a solid composition, one or more active ingredient(s) is (are) admixed with at least one inactive diluent such as lactose, mannitol, glucose, hydroxypropyl cellulose, microcrystalline cellulose, starch, polyvinyl pyrrolidone, magnesium aluminate metasilicate. According to a conventional procedure, a composition may contain additives other than the inactive diluent, for example, lubricant such as magnesium stearate; disintegrator such as cellulose calcium gluconate; and stabilizer, for example, etherificated cyclodextrin such as xcex1, xcex2, and xcex3-cyclodextrin, or dimethyl-xcex1-, dimethyl-xcex2-, trimethyl-xcex2-, and hydroxypropyl-xcex2-cyclodextrin, branched cyclodextrin such as glycosyl-, maltosyl-cyclodextrin, formilated cyclodextrin, sulfur-containing cyclodextrin, misoprotol (phonetic), and phospholipid. When any of the above described cyclodextrin is used, there is a case where a clathrate inclusion compound is formed from the cyclodextrin to increase the stability of a composition. Furthermore, there is a case when liposome is formed by utilizing phospholipid, the stability of the resulting product increases. If desired, tablet or pill may be covered or coated with a film or two or more layers made of a substance soluble in ventriculus or intestine such as saccharose, gelatin, hydroxypropyl cellulose, and hydroxypropyl methyl cellulose phthalate. Furthermore, a composition may be formed in capsule by the use of a disintegrable material such as gelatin. In case of requiring fast-acting property, a composition may be formed in sublingual tablet.
As a base, glycerin, lactose and the like may be used. An example of liquid compositions for oral administration includes emulsion, solution, suspension, syrup, and elixir formulations. They may contain an inactive diluent used ordinarily such as purified water, and ethanol. Any of these compositions may further contain an additive such as wetting agent, and suspending agent; edulcorant; flavoring material, aromatic, and preservative in addition to the inactive diluents.
As another composition for oral administration, there is a spraying agent containing one or more active ingredient(s) and being formulated in accordance with a manner which itself has been well known.
An example of parenteral solutions according to the present invention includes sterile aqueous or nonaqueous solution, suspension, and emulsion. An example of media for the aqueous solution and the suspension includes distilled water for injection, physiological saline, and Ringer solution.
An example of diluent for the nonaqueous solution and the suspension includes propylene glycol, polyethylene glycol, vegetable oils such as olive oil, alcohols such as ethanol, polysorbate and the like. These compositions may further contain adjuvants such as preservative, wetting agent, emulsion, and dispersant. They are sterilized by, for example, filtration passing them through a bacteria remaining filter, incorporation of a bacteriocide, gas sterilization, or radiation sterilization. They may also be manufactured in the form of a sterile solid composition, and it is dissolved in sterile water or a sterile solvent for injection prior to the application therefor.
Another form for such compositions is suppository or vaginal suppository. These suppositories may be prepared by admixing an active ingredient with a base such as cacao butter or the like which softens at body temperature, and in this case, a nonionic surfactant having a suitable softening temperature may be added further to improve the absorption thereof.